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GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition

Since December 2019, SARS-CoV-2 has spread quickly worldwide, leading to more than 280 million confirmed cases, including over 5,000,000 deaths. Interestingly, coronaviruses were found to subvert and hijack autophagic process to allow their viral replication. Autophagy-modulating compounds thus rapi...

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Autores principales: Bestion, Eloïne, Zandi, Keivan, Belouzard, Sandrine, Andreani, Julien, Lepidi, Hubert, Novello, Marie, Rouquairol, Clara, Baudoin, Jean-Pierre, Rachid, Madani, La Scola, Bernard, Mege, Jean-Louis, Dubuisson, Jean, Schinazi, Raymond F., Mezouar, Soraya, Halfon, Philippe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778678/
https://www.ncbi.nlm.nih.gov/pubmed/35062337
http://dx.doi.org/10.3390/v14010132
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author Bestion, Eloïne
Zandi, Keivan
Belouzard, Sandrine
Andreani, Julien
Lepidi, Hubert
Novello, Marie
Rouquairol, Clara
Baudoin, Jean-Pierre
Rachid, Madani
La Scola, Bernard
Mege, Jean-Louis
Dubuisson, Jean
Schinazi, Raymond F.
Mezouar, Soraya
Halfon, Philippe
author_facet Bestion, Eloïne
Zandi, Keivan
Belouzard, Sandrine
Andreani, Julien
Lepidi, Hubert
Novello, Marie
Rouquairol, Clara
Baudoin, Jean-Pierre
Rachid, Madani
La Scola, Bernard
Mege, Jean-Louis
Dubuisson, Jean
Schinazi, Raymond F.
Mezouar, Soraya
Halfon, Philippe
author_sort Bestion, Eloïne
collection PubMed
description Since December 2019, SARS-CoV-2 has spread quickly worldwide, leading to more than 280 million confirmed cases, including over 5,000,000 deaths. Interestingly, coronaviruses were found to subvert and hijack autophagic process to allow their viral replication. Autophagy-modulating compounds thus rapidly emerged as an attractive strategy to fight SARS-CoV-2 infection, including the well-known chloroquine (CQ). Here, we investigated the antiviral activity and associated mechanism of GNS561/Ezurpimtrostat, a small lysosomotropic molecule inhibitor of late-stage autophagy. Interestingly, GNS561 exhibited antiviral activity of 6–40 nM depending on the viral strain considered, currently positioning it as the most powerful molecule investigated in SARS-CoV-2 infection. We then showed that GNS561 was located in lysosome-associated-membrane-protein-2-positive (LAMP2-positive) lysosomes, together with SARS-CoV-2. Moreover, GNS561 increased LC3-II spot size and caused the accumulation of autophagic vacuoles and the presence of multilamellar bodies, suggesting that GNS561 disrupted the autophagy mechanism. To confirm our findings, we used the K18-hACE2 mouse model and highlighted that GNS561 treatment led to a decline in SARS-CoV-2 virions in the lungs associated with a disruption of the autophagy pathway. Overall, our study highlights GNS561 as a powerful drug in the treatment of SARS-CoV-2 infection and supports the hypothesis that autophagy blockers could be an alternative strategy for COVID-19.
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spelling pubmed-87786782022-01-22 GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition Bestion, Eloïne Zandi, Keivan Belouzard, Sandrine Andreani, Julien Lepidi, Hubert Novello, Marie Rouquairol, Clara Baudoin, Jean-Pierre Rachid, Madani La Scola, Bernard Mege, Jean-Louis Dubuisson, Jean Schinazi, Raymond F. Mezouar, Soraya Halfon, Philippe Viruses Article Since December 2019, SARS-CoV-2 has spread quickly worldwide, leading to more than 280 million confirmed cases, including over 5,000,000 deaths. Interestingly, coronaviruses were found to subvert and hijack autophagic process to allow their viral replication. Autophagy-modulating compounds thus rapidly emerged as an attractive strategy to fight SARS-CoV-2 infection, including the well-known chloroquine (CQ). Here, we investigated the antiviral activity and associated mechanism of GNS561/Ezurpimtrostat, a small lysosomotropic molecule inhibitor of late-stage autophagy. Interestingly, GNS561 exhibited antiviral activity of 6–40 nM depending on the viral strain considered, currently positioning it as the most powerful molecule investigated in SARS-CoV-2 infection. We then showed that GNS561 was located in lysosome-associated-membrane-protein-2-positive (LAMP2-positive) lysosomes, together with SARS-CoV-2. Moreover, GNS561 increased LC3-II spot size and caused the accumulation of autophagic vacuoles and the presence of multilamellar bodies, suggesting that GNS561 disrupted the autophagy mechanism. To confirm our findings, we used the K18-hACE2 mouse model and highlighted that GNS561 treatment led to a decline in SARS-CoV-2 virions in the lungs associated with a disruption of the autophagy pathway. Overall, our study highlights GNS561 as a powerful drug in the treatment of SARS-CoV-2 infection and supports the hypothesis that autophagy blockers could be an alternative strategy for COVID-19. MDPI 2022-01-12 /pmc/articles/PMC8778678/ /pubmed/35062337 http://dx.doi.org/10.3390/v14010132 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bestion, Eloïne
Zandi, Keivan
Belouzard, Sandrine
Andreani, Julien
Lepidi, Hubert
Novello, Marie
Rouquairol, Clara
Baudoin, Jean-Pierre
Rachid, Madani
La Scola, Bernard
Mege, Jean-Louis
Dubuisson, Jean
Schinazi, Raymond F.
Mezouar, Soraya
Halfon, Philippe
GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition
title GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition
title_full GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition
title_fullStr GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition
title_full_unstemmed GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition
title_short GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition
title_sort gns561 exhibits potent antiviral activity against sars-cov-2 through autophagy inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778678/
https://www.ncbi.nlm.nih.gov/pubmed/35062337
http://dx.doi.org/10.3390/v14010132
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